I'm pretty sure secretin works for this imaging application. In retrospect they should have used more than three readers in their trial design. (Don't know what the problems with their CRO was). Sounds like the FDA and the EMEA are open to a blinded re-read.

The alternative to secretin-enhanced imaging is a diagnostic procedure (ERCP) with quite substantial morbidity (acute pancreatitis).

Even if approved we aren't talking a blockbuster product here, but it would be significant on top of the existing Protein A business given the company's small market cap.

Peter

Reminds me of an old cartoon:

Picture is of two young guys strung up in a cornfield, arms stretched out, acting as scarecrows. The one is saying:
"Eng. Lit. And you?"

Peter

I show a bunch of sales (maybe 6k shares worth) all at 12:16:48 at $7.00. There were also a few hundred at the same time at higher prices (up to $9.90) interspersed among them.

Maybe the lesson here is to keep some very low limit bids in place on any stocks one is interested in. I would have re-entered myself if I could have gotten sub-$10 shares.

Peter

Clearly 534 is going to be first line treatment out of the gate for patients with the T315I mutation - nothing else works.

The projected trial would be presumably be high-risk patients determined by their Sokal score (a composite of age, spleen size and some blood counts). That would indeed be an expensive trial, if only because they would have to pay for the Gleevec or other comparator and because the trial would be fairly large and lengthy. About 70% of high-risk patients eventually (24 months) respond (CCyR) to Gleevec, vs. 90% for low-risk patients so you are going up against a treatment that works pretty well even in high-risk patients.

If they don't partner, that would slow down development of the drug in non-CML indications.

Peter

No - that was the number of responders in the high dose group. All the groups had 38 or 39 patients, but they combined two groups in part of the analysis.

The recent HGSI study doesn't show anything in the way of dose response at 76 weeks - if anything the 1 mg/kg group did better than the 10 mg/kg group:

Based on an intention-to-treat (ITT) analysis, patient response rates for belimumab plus standard of care versus placebo plus standard of care, as measured by the SLE Responder Index (SRI) at Week 76, were: 38.5% for 10 mg/kg belimumab, 39.1% for 1 mg/kg belimumab, and 32.4% for placebo (p=0.13 and p=0.11 for 10 mg/kg and 1 mg/kg belimumab, respectively vs. placebo). The SRI defines patient response as an improvement in SELENA SLEDAI score of 4 points or greater, with no clinically significant BILAG worsening and no clinically significant worsening in Physician's Global Assessment.
Topline Week 76 results currently available for secondary endpoints include:
¦The proportion of patients with a reduction in SELENA SLEDAI score of at least 4 points was 41.4% for belimumab 10 mg/kg, 42.1% for belimumab 1 mg/kg, and 33.8% for placebo (p=0.066 and p=0.049 for belimumab 10 mg/kg and 1 mg/kg, respectively vs. placebo).
¦Mean improvement from baseline in Physician's Global Assessment (PGA) was 0.51 for belimumab 10 mg/kg, 0.53 for belimumab 1 mg/kg, and 0.49 for placebo (p=0.21 for both belimumab 10 mg/kg and for 1 mg/kg, vs. placebo).
¦At entry into the BLISS-76 study, approximately 46% of patients were receiving steroids at a prednisone-equivalent dose of at least 7.5 mg per day. Among these patients, the percentage of patients who had their average steroid dose reduced by at least 25% from baseline to 7.5 mg per day or less during the last 12 weeks of the study (Week 64 through Week 76) was 24.2% for belimumab 10 mg/kg, 26.9% for belimumab 1 mg/kg, and 17.5%% for placebo (p=0.27 and p=0.07 for belimumab 10 mg/kg and 1 mg/kg, respectively, vs. placebo.
¦In BLISS-76 at Week 76, the mean percent reduction in SELENA SLEDAI score was 37.0% for belimumab 10 mg/kg, 36.1% for belimumab 1 mg/kg, and 27.8% for placebo (p=0.01 and p=0.03 for 10mg/kg belimumab and 1 mg/kg belimumab, respectively vs. placebo). At Week 52, the reduction in SELENA SLEDAI was 36.0% for belimumab 10 mg/kg, 33.9% for belimumab 1 mg/kg, and 26% for the placebo (p<0.01 and p=0.04 for 10 mg/kg and 1 mg/kg belimumab, respectively vs. placebo).

I wouldn't write off the IMMU drug by any means - clearly more testing is needed. But if I recall correctly (I don't really follow IMMU) the potential economics if the drug is successful are quite different than they are for HGSI.

Peter

I agree, and admit to being mistaken about my skepticism that ARIA would actually get cash out of a restructured deal. Merck must be fairly confident that the drug is for real.

Basically this is a deal along the lines that they should have struck in the first place.

The fact that Merck now has complete control of development is also good.

Net result of this restructuring is to make the company a purer play on 534 and the ALK inhibitor and to remove short-term finance risk.

Peter

Yes, you are correct - I elided two steps into one in my step 3.

They first improved the compound using standard methodology and only then determined the common resistance which gave the clue as to their mutual target.

Peter

They weren't trying to find a part of the genome that couldn't mutate - they were just trying to determine what the target of their two drugs was. The fact that both drugs produced changes in parts of NS5A and these changes conferred resistance to the drugs confirmed that NS5A was indeed the target.

Their actual drug candidate seems potent enough to cope with any single point substitutions - you do get resistance in the sense of needing a higher dose, but still within the therapeutic range. (And the resistant species appear to be less fit to boot).

Peter

My recollection is that the patient stopped for reasons unrelated to the drug.

The article wasn't about 790052, more about the process whereby they discovered the target and developed the precursors to 790052.

JOURNAL OF VIROLOGY, Jan. 2010, p. 482–491 Vol. 84, No. 1
0022-538X/10/$12.00 doi:10.1128/JVI.01360-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Identification of Hepatitis C Virus NS5A Inhibitors

Julie A. Lemm,1* Donald O’Boyle II,1 Mengping Liu,1 Peter T. Nower,1 Richard Colonno,1†
Milind S. Deshpande,2‡ Lawrence B. Snyder,2 Scott W. Martin,2 Denis R. St. Laurent,2
Michael H. Serrano-Wu,2§ Jeffrey L. Romine,2 Nicholas A. Meanwell,2 and Min Gao1
Department of Virology,1 and Discovery Chemistry,2 Bristol-Myers Squibb Research & Development, Wallingford, Connecticut
Received 2 July 2009/Accepted 25 September 2009
Using a cell-based replicon screen, we identified a class of compounds with a thiazolidinone core structure
as inhibitors of hepatitis C virus (HCV) replication. The concentration of one such compound, BMS-824, that
resulted in a 50% inhibition of HCV replicon replication was
5 nM, with a therapeutic index of >10,000. The
compound showed good specificity for HCV, as it was not active against several other RNA and DNA viruses.
Replicon cells resistant to BMS-824 were isolated, and mutations were identified. A combination of amino acid
substitutions of leucine to valine at residue 31 (L31V) and glutamine to leucine at residue 54 (Q54L) in NS5A
conferred resistance to this chemotype, as did a single substitution of tyrosine to histidine at amino acid 93
(Y93H) in NS5A. To further explore the region(s) of NS5A involved in inhibitor sensitivity, genotype-specific
NS5A inhibitors were used to evaluate a series of genotype 1a/1b hybrid replicons. Our results showed that,
consistent with resistance mapping, the inhibitor sensitivity domain also mapped to the N terminus of NS5A,
but it could be distinguished from the key resistance sites. In addition, we demonstrated that NS5A inhibitors,
as well as an active-site inhibitor that specifically binds NS3 protease, could block the hyperphosphorylation
of NS5A, which is believed to play an essential role in the viral life cycle. Clinical proof of concept has recently
been achieved with derivatives of these NS5A inhibitors, indicating that small molecules targeting a nontraditional
viral protein like NS5A, without any known enzymatic activity, can also have profound antiviral effects
on HCV-infected subjects.

There is some brief discussion about what NS5A does for the virus, but I think this is not well understood yet.

Well here is my understanding of what they did:

1. They used a cell-based HCV replicon and did a high-throughput screen against the deck of BMS compounds (with some sort of normal cell-based control so they weren't just picking toxic compounds). So right off that's a very expensive and ambitious project, and of course non-pharma companies don't have access to a comparable set of compounds.

2. In the screening, they found a modest potency compound that they then used to produce some HCV cell lines that were resistant to it.

3. They then did some SAR analysis which enabled them to find a much more potent compound to which the above resistant cell lines were also resistant.

4. They then analyzed where the HCV had mutated so as to become resistant to both these compounds, and this analysis together with the structure of the two compounds revealed that NS5A was their mutual target.

That of course came as a surprise to them, as NS5A had no enzymatic activity and an unknown function.

(I might have gotten some of this wrong as I'm going by memory from a very dense article I skimmed a couple of weeks back).

I have no idea if anyone has ever done something similar before (either in HCV or perhaps HIV) - I've always been quite unclear as to where targets come from. Presumably this methodology would only work for a rapidly mutating virus. But seems like a very nice piece of work even if it wasn't totally original.

Peter

The other interesting question is whether any of these other programs even have freedom to operate in this area. It was BMS that discovered the NS5A target in the first place, and I'm guessing they made every effort to lock up the space.

Incidentally the ingenious way they originally discovered the importance of NS5A illustrates that big pharma really is still good for something - I don't think it was anything a smaller company would ever have even tried, let alone succeeded at. A really impressive piece of research.

Peter

Any entrants are going to have a tough time competing with this BMY entrant - not often you see such striking single-dose numbers:

Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect

Min Gao1, Richard E. Nettles2, Makonen Belema3, Lawrence B. Snyder3, Van N. Nguyen3, Robert A. Fridell1, Michael H. Serrano-Wu3, David R. Langley4, Jin-Hua Sun1, Donald R. O’Boyle II1, Julie A. Lemm1, Chunfu Wang1, Jay O. Knipe5, Caly Chien2, Richard J. Colonno1, Dennis M. Grasela2, Nicholas A. Meanwell3 & Lawrence G. Hamann3

1. Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA
2. Department of Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA
3. Department of Discovery Chemistry,
4. Department of Computer-Aided Drug Design,
5. Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA

Correspondence to: Nicholas A. Meanwell3 Correspondence and requests for materials should be addressed to N.A.M. (Email: Nicholas.Meanwell@bms.com).

Top of page
Abstract

The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200?million people1. Current therapy relies upon a combination of pegylated interferon-a and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus2, 3. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B4. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC50) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3?log10 reduction in mean viral load measured 24?h post-dose that was sustained for an additional 120?h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144?h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.


http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08960.html

Anyone here follow Becton, Dickinson? A value-oriented (non-biotech) investor I know was intrigued by them. Their needle business seems to be a great cash cow, but I have no idea if there are any competitive threats.

Peter

I concur with genisi that Erbitux hasn't been shown to helpful in K-RAS mutations in NSCLC (nor has anything else to my knowledge).

This article seems to be a good summary of state of play:

http://www.cancernetwork.com/cme/article/10165/1430608

I posted about the BATTLE trial on SI a couple of days ago - nice example of adaptive enrollment.

You can see the webcast here:

http://ow.ly/1zY89

Notable how well ONXX's Nexavar did in that trial, particularly with the KRAS mutations. But the market seems not to care, perhaps because the Nexavar combo trial in NSCLC previously failed, or perhaps because nobody is paying attention. But does give some encouragement for the current Nexavar NSCLC trials.

The Bert Vogelstein webcast (Conclusion: "We now understand cancer") is great:

http://ow.ly/1AGXf

I forgot to mention that Abraxis has a late-breaker, but that reflects a trial we already know about. But somehow they get no respect with the academic oncology community - I have no idea why, as their results seem compelling to me.

Aside from the usual suspects, Celldex could be an ASCO play - they have a number of abstracts. Micromet is always interesting, although it's gotten rather pricey and so I exited (but I could well see coming to regret that). PCYC has an abstract related to their BTK inhibitor in NHL that could be interesting. ZIOP has a late-breaker. ARQL seems interesting (but I don't own it).

But these stocks have pretty much all had biggish runs already, so who knows how much steam is left in the short run.

Peter

Thanks. I glanced through them and the only late-breaker I noticed with investment implications for a small-cap biotech was for ZIOP (in addition to the ARIA one previously referenced here).

(I might easily have missed one though, and of course late-breaker is no guarantee of positive results - Novelos has a late-breaker for its failed trial).

Peter

Thanks. Can you see any way to get a list of the LBA's?

The ASCO meeting site is up - but only the titles of abstracts are available:

http://meetingplanner.asco.org/

(and I assume titles of late-breakers are not available either).

Peter

>>Gammagard AD

I'd add that this is another "break the bank" and then some treatment - Gammagard is inherently extremely expensive to produce and administer and it's not even clear they could ramp up production by the two orders of magnitude or more (which would be needed if this were successful) even if they wanted to.

Incidentally Halozyme has a partnership w/ Baxter for an injectible form of Gammagard.

Peter

I'd agree that while it's an embarrassment it doesn't really change their chance of approval at the end of the day. It looks like it was a pretty arcane issue.

Still think that Vivus looks a better bet though.

Peter

>>ARIA Fidelity discloses 14.97% stake

Well that goes a long way towards explaining the move.

I believe Fidelity has moved away from their previous (stupid) staffing technique of rotating their portfolio managers through each of their specialty funds. Having non-biotech folks making biotech picks gets you mediocrity if you are lucky.

Peter

Well seeing they apparently found a cure for AD, I'm not surprised the stock surged:

http://seekingalpha.com/article/197650-did-star-scientific-just-find-a-cure-for-alzheimer-s-disease

One would think the suckers that buy on these pumps would soon be fleeced and move on to other ventures. This stock still has a market cap of over $300m (and I'm guessing there are bunches of warrants and the like out too).

Peter

I'd be very surprised if that were the case. All I am expecting is something that caps Aria's spend at reasonable levels. If I am correct, and we also accept management's assurances of no new raise, then a 534 partnership with a hefty upfront is likely also near.

Peter

The following article claims just that:




They claim in preclinical models no single resistant mutation develops when you give 534. There are multiple mutations that can confer resistance, and this of course (if correct) argues why 543 should indeed be front line. But it's a long way from preclinical claims like this to becoming standard front-line in the real world, particularly with Gleevec going generic.

Peter

>>Why would these institutions do this?

Because the stock is liquid, they purchased the shares at a substantial discount and got warrants. With very little risk, they can convert their preferred immediately, sell the resulting stock and walk away with a few cents a share plus the warrants.

Peter

Edit: Here's a quote from a recent filing by them. Note that because the preferred are in theory more valuable than the common, the only reason to convert is that you want to sell the shares immediately:

The key case to watch is in re Bilski which was argued before the Supreme Court last November but has not yet been decided. This relates to business method patents, but the Court of Appeals decision was very broad and restricted such patents to those making a "transformation" or involving a "machine." It was a very poor decision in my opinion, produced by judges that don't understand computers for one thing. (The notion that something could be an invention if you hardwire it, but not if you write a program to perform the exact same activity on a general-purpose computer is naive beyond words).

The court here followed Bilski in overruling the MYGN process patents here. Hopefully this decision will serve as a wake-up call to the Supreme Court about how much of an overreach the appeals court decision in Bilski was.

Anyhow, if the Supreme Court overrules or narrows Bilski, then tests for biomarkers and the like should again become patentable. I personally see no rationale for allowing a composition of matter patent for a gene though.

(BTW, Bilski was a really broad and stupid patent for hedging commodities that should never have been granted in the first place for other reasons).

Peter

Here are a list of expanded access programs registered at the clinicaltrials site:

http://www.clinicaltrials.gov/ct2/results?term=%22Expanded%20Access%22%20[STUDY-TYPES]&recr=Open

Peter

>>expanded access

The latest FDA rules on this are available here:

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm172492.htm

Peter

And coincidentally, today's NEJM has a publication of their results in this indication together with a supportive editorial.

Peter

It's not a silly question at all. Clearly there is some lag involved between any change in economic policy (including tax rates) and the actual impact on the economy.

If you are looking for an example that you would be happier with, the relationship between changes in cap gains rates and total cap gains tax collections is more interesting. There is a frequent claim by Reaganites that reducing the rate increased tax collections. What this overlooks is that people can time their capital gains, and so if rates are going to be rising, people take their gains and delay their losses. If rates will be falling, people do the opposite. So if you announce that you are cutting rates, expect a drop in collections before the rate cuts and an increase after the cut.

If cap gains rates rise to 20% (as I expect they will), I think you will see a rise in collections ahead of the change. That, together with the collections from Roth conversions this year and next, might provide a substantial "unexpected" rise in tax collections this year and next.

Peter

It's not a silly question at all. Clearly there is some lag involved between any change in economic policy (including tax rates) and the actual impact on the economy.

If you are looking for an example that you would be happier with, the relationship between changes in cap gains rates and total cap gains tax collections is more interesting. There is a frequent claim by Reaganites that reducing the rate increased tax collections. What this overlooks is that people can time their capital gains, and so if rates are going to be rising, people take their gains and delay their losses. If rates will be falling, people do the opposite. So if you announce that you are cutting rates, expect a drop in collections before the rate cuts and an increase after the cut.

If cap gains rates rise to 20% (as I expect it will), I think you will see a rise in collections ahead of the change. That, together with the collections from Roth conversions this year and next, might provide a substantial "unexpected" rise in tax collections this year and next.

Peter

Just to put that in context, they have some 590 million shares outstanding (assuming that number isn't out of date already, and ignoring who knows how many warrants) plus some $70m in debt. So a total enterprise value north of $400m even though they will need to raise yet more money soon.

Single-handedly keeping Rodman in business?

Peter

It's not like NVS/MNTA can tell the FDA "Our drug is made using the same process that Teva uses - this we know for sure, because we stole their trade secrets."

If the process is indeed (to at least some extent) a trade secret, then I don't see how MNTA can establish that their process is identical to the Teva process, and you are back to showing the drugs are the "same."

But if you patent something, then you have to show how to enable the patent, so I remain unclear of the exact role of the trade secrets here. Clearly the process is not fully disclosed in the patent, otherwise others without MNTA's technology could also copy it easily.

Peter

Yes I could see that would work. But how do you demonstrate sameness of the process given that the specific process used is presumably a Teva trade secret? I'm assuming you can't conclude that the processes are the same simply because some finite set of tests can't distinguish the end product of the two processes - that would be circular.

(I'm not altogether clear the extent to which trade secrets and patents can co-exist, and maybe that plays into the picture too).

Peter

Even though it's 100% synthetic, isn't it the case for Copaxone that (quoting from link below) "probably no two molecules are completely identical"?

So proving it's "the same" has to be challenging given there is no "same" there. Sure they can devise a bunch of tests to attempt to show it's indistinguishable from various lots of the branded drug, but given that the underlying drug is (in some real sense) impossible to characterize, will the FDA view this as enough? Maybe the next test you tried would show a difference.

I'm admittedly out of my depth here, so could well be I have this wrong.

Here's the link I mentioned above:

"The Chemistry of the Copaxone Drug"

http://www.weizmann.ac.il/ICS/booklet/1/pdf/copaxon.pdf

Peter

Well it wasn't just retail investors. Somehow he kept on selling big chunks of stocks in various offerings. Even if those buyers were already short or dumped after the offering those shares were presumably going to end up on the open market one way or another. Note the effective market cap is even higher because of the short position, not to mention the warrants etc.

Peter

The Feuerstein live blog was very revealing - not for the content of the meeting which wasn't at all unexpected, but for the numbers and views of people who followed it - nearly 21,000 he claims.

I guess that's my partial answer to what's been holding CTIC up. But who attracted all these retail folks to the stock in the first place? Is there some Svengali-like stock pumper out there that has all these folks in thrall?

Peter

Not only is the CTIC data bad, but they don't seem to be that well prepared:

Bianco's ego maybe led him to present himself.

Many years back I believed pixantrone was a good drug - maybe it still is, but this trial sure didn't show it. I will confess to betting wrong on their previous taxol-like drug (now called Opaxio) - I was seduced by the unusually long time the trial was taking until the requisite number of events were in. But I've been short the stock for a few months now and it looks like I should recoup most of my losses from several years ago.

Peter